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Phosphodiesterase 6 Generates Intracellular Cgmp Microdomains in the Native Endothelium

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Phosphodiesterase 6 Generates Intracellular Cgmp Microdomains in the Native Endothelium Phosphodiesterase 6 generates intracellular cGMP microdomains in the native endothelium BY FATMA ELJETLAWI Submitted to the Faculty of Medecine in Partial Fulfullment of the Requirements for the Degree of Master of Science Department of Molecular and Integrative Physiology Université de Montréal Montreal, Quebec July 2016 © Fatma Eljetlawi, 2016 All rights reserved. Résumé Les cellules endothéliales (CEs) participent au maintien de l’homéostasie vasculaire en générant et libérant de nombreux agents bioactifs, incluant l’oxyde nitrique (NO). Le NO module plusieurs fonctions vasculaires telles que le tonus et la perméabilité vasculaire via la stimulation de la guanylate cyclase soluble (GCs) provoquant la formation de GMPc. D’autre part, les phosphodiestérases (PDEs) sont des enzymes métabolisant les nucléotides cycliques (GMPc et AMPc) et participent donc à des étapes essentielles du contrôle des voies de signalisation du GMPc et de l’AMPc. Bien que les CEs soient la source principale de NO, la voie de signalisation NO-GMPc endothéliale et les répercussions fonctionnelles demeurent méconnues. Nous avons alors émis l’hypothèse qu’une population spécifique de PDEs ciblant le GMPc (PDEs-GMPc) permettrait aux CEs de maintenir des niveaux de GMPc faible malgré l’importante production de NO. L’expression des isoformes de PDEs-GMPc dans les artères mésentériques de souris fut initialement déterminée. PDE5 et PDE6 furent détectées tant sous la forme d’ARNm que de protéines dans les artères natives alors que PDE6 est absente de lignées de CEs en culture. La distribution intracellulaire des deux enzymes est distincte. Alors que PDE5 est distribué uniformément dans le cytoplasme des cellules endothéliales, les sous- unités catalytiques de PDE6 (α et β) sont préférentiellement présentes dans la région péri- nucléaire. Ces résultats suggèrent que PDE6 puisse être impliqué dans le contrôle de microdomaines de GMPc. Des simulations effectuées à l’aide d’un modèle mathématique développé sur la base de ces données sont en accords avec la notion selon laquelle l’expression et la distribution subcellulaire de PDE6 sont responsables de microdomaines de GMPc dans l’endothélium. En absence de PDE6, l’ajout de NO sous forme de bolus unique ou répétée mène à une augmentation homogène de la concentration cytoplasmique en GMPc malgré la présence de PDE5. Toutefois, la présence de PDE6 à la membrane péri-nucléaire crée un espace péri-nucléaire pauvre en GMPc. Les résultats de cette étude forment les premières évidences de l’expression et de la distribution intracellulaire hétérogène de PDE6 dans les cellules endothéliales natives et suggèrent leur implication dans la génération de microdomaines. Keywords: cGMP, PDE5, PDE6, modèle mathématique, microdomaines. i Abstract Endothelial cells (EC) are essential regulator of vascular homeostasis through the generation and release of various bioactive agents, including nitric oxide (NO). NO modulates several vascular functions such as vascular tone and permeability, through the stimulation of soluble guanylate cyclase (sGC) leading to the production of cGMP. Conversely, phosphodiesterases (PDEs) are enzymes metabolizing cyclic nucleotides (cGMP and cAMP) and are therefore major regulatory players for cGMP and cAMP signalling pathways. Although ECs are the main source of NO, little is known on the endothelial NO-cGMP signalling pathway and cellular outcomes. It was then hypothesized that a specific population of cGMP-phosphodiesterases allows ECs to stabilize cGMP levels despite the elevated production of NO. Expression of cGMP-phosphodiesterases was initially studied in resistance mesenteric arteries from mice. PDE5 and PDE6 were both found at mRNA and protein levels in native arteries but PDE6 is not found in cultured ECs. Interestingly, subcellular distributions of both enzymes were distinct. PDE5 appeared to be homogeneously distributed whilst PDE6 catalytic subunits (PDE6α and PDE6β) showed a preferential staining in the perinuclear region. These results suggest that PDE6 might be involved in the regulation of cGMP microdomains. Based on these findings, a mathematical model was developed. Simulations of dynamic cGMP levels in ECs support the notion of cGMP microdomains dependent on PDE6 expression and localization. In the absence of PDE6, application of NO either as a single bolus or repetitive pulses led to a homogeneous increase in cGMP levels in ECs despite PDE5 homogeneous distribution. However, PDE6 subcellular targeting to the perinuclear membrane generated a cGMP-depleted perinuclear space. The findings from this study provide the first evidence of the expression and specific intracellular distribution of PDE6 in native endothelial cells that strongly support their involvement in the generation of cGMP microdomains. Keywords: cGMP, PDE5, PDE6, mathematical model, microdomains. ii Table of contents Page Resume ....................................................................................................................................... i Abstract ..................................................................................................................................... ii Contents ................................................................................................................................... iii List of figures ............................................................................................................................ v List of tables............................................................................................................................. vi List of abbreviations .............................................................................................................. vii Acknowledgements ................................................................................................................. ix Chapter 1. Introduction........................................................................................................... 1 1. Blood vessels ....................................................................................................................... 1 1.1 Structure ............................................................................................................................ 1 1.1.1 Smooth muscle cells .................................................................................................. 2 1.1.1.1 Structure .................................................................................................................. 3 1.1.1.2 Function .................................................................................................................. 3 1.1.2 Endothelial cells ........................................................................................................ 4 1.1.2.1 Structure .................................................................................................................. 4 1.1.2.2 Function .................................................................................................................. 5 1.1.3 Endothelial-smooth muscle communication ............................................................. 8 1.2 Regulation of blood vessel diameter ................................................................................. 9 1.2.1 Mechanism of cAMP dependent vasodilation ........................................................ 10 1.2.2 Mechanism of cGMP dependent vasodilation ........................................................ 11 1.3 NO-cGMP-PKG-pathway ............................................................................................... 11 1.3.1 Nitric oxide synthetase (NOS) ................................................................................ 11 1.3.1.1 Classification of nitric oxide synthetase (NOS) ................................................... 11 1.3.1.2 eNOS activation .................................................................................................... 12 1.3.2 Nitric oxide (NO) .................................................................................................... 12 1.3.2.1 Nitric oxide as a signalling molecule ................................................................... 12 1.3.2.2 Cardiovascular effects of NO ............................................................................... 13 iii 1.3.3 Guanylate cyclases .................................................................................................. 14 1.3.4 cGMP ...................................................................................................................... 14 1.3.5 PKG ......................................................................................................................... 16 1.3.6 Phosphodiesterases .................................................................................................. 16 1.3.6.1 PDE5 ..................................................................................................................... 20 1.3.6.1.1 Structure ....................................................................................................... 20 1.3.6.1.2 Pharmacology ............................................................................................... 22 1.3.6.2 PDE6 ..................................................................................................................... 22 1.3.6.2.1 Structure ....................................................................................................... 23 1.3.6.2.2 Activation
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